The Nodulus and Uvula (NU) are regions of the cerebellar cortex essential for vestibular processing and spatial navigation. They process motion signals arriving from the vestibular organs (otoliths and semicircular canals), and send outputs to cerebellar and brainstem vestibular nuclei. The long-term goal of this project is to understand the role of the NU in spatial navigation and vestibular processing. Recently it has been shown that NU Purkinje cells (the sole output of the cerebellar cortex) exclusively encode inertial motion (translation) by combining otolith signals with a transformed signal from the semicircular canals. It is still unknown however, whether translation is computed within the NU or it is sent there already computed by its inputs, e.g. from the vestibular nuclei. This grant proposal is designed to tackle this question, specifically to investigate the role of GABAergic interneurons within the NU in computing translation. The specific aim of this project is to test the hypothesis that GABAergic interneurons in the cerebellar NU participate in the transformation of head- centered vestibular afferent information into inertial motion. For this purpose, the vestibular properties of NU Purkinje cells will be characterized with and without application of GABA-A (aim 1a), GABA-B (aim 2b) and combined GABA-A and GABA-B (aim 1c) receptor antagonists during translation, rotation and their combinations. These drugs will be delivered iontophoretically with small current injections (50-100nAmp), and are likely to spread less than 100 microns, thus affecting only synapses near the recorded Purkinje cell. The project focuses on studying the effect of blocking GABA-A and GABA-B receptors because they are the most common forms of GABA receptors in the cerebellar cortex. The three proposed experimental manipulations (1a, 1b and 1c) are designed to complement each other and strengthen the power of interpretation. For instance, studying the effect of blocking GABA-A and GABA-B receptors separately and in combination allows testing the possibility that they belong to pathways performing different computations, or that they work to complement each other in order to compute translation. Based on preliminary data, blockage of GABAergic inhibition will remove the ability of NU Purkinje cells to discriminate tilt from translation, and will affect the temporal and spatial properties of vestibular signals (otolith and canal signals). Together, these experiments will elucidate the role of inhibitory interneurons in the signal transformations carried out by the NU and have the potential of unveiling general rules of cerebellar function. Furthermore, a better understanding NU function could lead to the development of therapies for rehabilitation following disease and trauma of the vestibular organs or the cerebellar cortex. PUBLIC HEALTH RELEVANCE: We move through our environment with ease unaware that for proper navigation our brain must perform high- level computations, such as distinguishing when we move from when we change our orientation with respect to gravity. A key structure for these computations is the cerebellar Nodulus and Uvula, and this grant proposal is designed to evaluate the role of this structure, specifically its inhibitory local network, in vestibular processing. The outcome of this research will provide insights into cerebellar function, which is a necessary step towards developing therapies for rehabilitation after trauma and disease of the vestibular sensory organs or related structures in the central nervous system.